1-({60 -Carboxymethoxybenzoyl-2-(2{40 -pyridyl)benzimidazoles

ABSTRACT

1-Aroylbenzimidazoles and 1-aroylbenzotriazoles and their use as antiinflammatory agents in the treatment of arthritic disorders.

United States Patent Sarges Feb. 4, 1974 1 1-(d-CARBOXYMETHOXYBENZOYL-2-(2'- PYRIDYUBENZIMIDAZOLES [56] References Cited [75] Inventor: Reinhard Surges, Old Mystic, Conn. U I D STATES PATENTS 3,055,907 9/1962 Brown et a1. 260/3092 [73] Ass'gnee' New 3,336,192 8/1967 5616116161. 260/302 H [22] Filed: Apr, 9, 1973 3,429,890 2/1969 Sletzinger et a1. 260/302 H 3,47 ,508 10 1969 t 1. 260 302 H 21 App]. No.: 349,222 1 a Related US. Application Dat Primary Examiner-Alan L. Rotman [62] Division Of S61. No. 186,446, 0C1. 4, 1971, Pat. N0. Firm-molly and Hum 3,751,428, which is a division Of S61. NO. 714,416, March 20, 1968, Pat. NO. 3,625,954. [57 ABSTRACT l-Aroylbenzimidazoles and l-aroylbenzotriazoles and [52] US. Cl. 260/295 B, 260/308 B, 260/3092,

260/473 A, 260/473 R, 424/263, 424/273 g g flfi fi fgig lg agents the treatment [51] Int. Cl C07d 31/44 I [58] Field of Search 260/295 B, 302 H, 309.2 2 Claims, N0 ng 1-(a-CARBOXYMETHOXYBENZOYL-Z-(2 PYRIDYL)BENZIMIDAZOLES CROSS-REFERENCE TO RELATED APPLICATIONS This application is a division of application Ser. No. 186,446, filed Oct. 4, 197], now US. Pat. No. 3,751,428 which, in turn, is a division of application Ser. No. 7I4,4l6 filed Mar. 20, I968 and now US. Pat. No. 3,625,954.

BACKGROUND OF THE INVENTION This invention relates to a series of novel I- aroylbenzimidazoles and l-aroylbenzotriazoles having valuable therapeutic properties. In particular, this invention is concerned with the preparation of novel 1- aroylbenzimidazoles and l-aroylbenzotriazoles possessing antiinflammatory activity in mammals.

Although l-benzoylbenzimidazole, l-benzoylbenzotriazole and a limited number of other substituted 1- aroyl benzimidazoles and benzotriazoles are known, the compounds of the present invention have now been prepared for the first time.

The discovery and preparation of therapeutic agents effective in alleviating arthritic disorders presents a formidable challenge, particularly in view of the fact that its etiology and pathogenosis are not presently fully understood, although various theories regarding the cause of the disease have been advanced. Human arthritic disorders, particularly rheumatoid arthritis, are evidenced by swelling, pain, tenderness, and inflammation of the joints. During the early stages of the disease, the joints usually appear red and contain considerable amounts of fluid.

Various antiinflammatory agents, e.g., the salicylates, have been found to alleviate the subacute symptoms of the arthritis and have been widely used therapeutically to treat subjects afflicted with the disease.

Many of the compounds described in the instant invention inhibit artificially induced edema formation in rats, a property which is considered by those skilled in the art as being indicative of a compounds potential usefulness as an antiinflammatory agent in the treatment of arthritic disorders.

SUMMARY OF THE INVENTION This invention comprises the preparation of novel I- aroylbenzimidazoles and l-aroylbenzotriazoles having anti-inflammatory activity. Among the novel I- aroylbenzimidazoles described herein are those having the following structural formulas:

2 wherein R can be CH CO H, Cl. and Br; R can be CFs. NHCOCE and --CH- CH CO H and R can be either H. Cl, or Br;

R can be either --CH or OCH R may be either H or CH;,; and

R can be CO H, N(CHs)z, OCH CO H, or

OCH CO CH C H provided that R is CH O when R is H;

g/\ 2-1 l ll 7 r; R

wherein R is either Z-pyridyl or CF and R is either Cl, Br, or OCH CO H.

The l-aroylbenzotriazoles included within the instant invention include those having the structural formulas:

DETAILED DESCRIPTION OF THE INVENTION The l-aroylbenzimidazoles and laroylbenzotriazoles of the present invention are conveniently prepared by reacting the appropriate benzimidazole or benzotriazole with an aroyl halide, preferably the chloride, in an inert anhydrous solvent in the presence of an organic base. Among the many solvents that may be employed are benzene, dialkyl ethers, and tet rahydrofuran. We have found tetrahydrofuran to be a convenient solvent with these reactions. The preferred organic bases include the trialkylamines such triethylamine. Where the benzimidazole or benzotriazole contains a carboxy group in the phenyl portion of the molecule. it is preferred to use up to 2 moles of organic base for every mole of aroyl halide used; although it should be understood that this aspect of the reaction is not critical. In those situations where it is desired to prepare a l-aroylbenzimidazole containing a carhoxyl function, e.g.. CO H and OCH CO H, in the aroyl portion of the compound, the preferred synthetic scheme is to aroylate the benzimidazole with an aroyl halide containing the benzyl ester of the desired carboxy functionality and then remove the benzyl group of the resultant compound by hydrogenolysis to provide the desired compound.

Thus, for example, the procedure in Chart I has been used in preparing a l-aroylbenzimidazole containing a OCH CO H functionality in the l-aroyl moiety.

CHART I Preparation of Intermediates CO H acted with a benzyl haloacetate in the presence of so-' dium or potassium hydride to give the diester A (see Chart l). which is usually not isolated and purified. but is converted with trifluoroacetic acid to the substituted benzoic acid B, shown in Chart I. This latter compound is converted tovthe corresponding acid halide C, which is used to benzoylate the benzimidazoles and benzotriazoles. If desired. the benzyl group in the ester moiety of the resultant compounds can be easily removed by hydrogenolysis to the corresponding acid functionality. l.e., OCH CO H.

A similar procedure is followed where it is desired to prepare a carboxy-containing l-aroyl moiety. Thus, the monoester of a phthalic acid is converted to the corresponding acid chloride. which is then used for aroylation. Here again. after the l-aroylbenzimidazole is prepared, the carbobenzoxy group is easily transformed into the corresponding carhoxy group by hydrogenolysls.

Similarly, we prefer to prepare the l-aroy|-2-(2- carboxyethyl)benzimidazole by first aroylating the benzyl ester of the 2-(2'-carboxyethyl)benzimidazole and C02 3 Butyl isobutylene OH BICHQCOQCHQCQIEE NaH 00 t Butyl OCH2CO2CH2C6H5 F5C02E r y a OCHQCOQCHECQIE E2139 2 2 2 6 5 A hydroxybenzoic acid is converted to the corresponding t-butyl ester by reaction with isobutylene in then converting the benzyl ester moiety of the resultant compound to the carboxy functionality by hydrogenolthe presence of a mineral acid. The ester is then re- 60 ysis.

N L CH CE COQCH C6E5 chloride In those cases where the phenyl group of the 2-(2 carboxyethyl)benzimidazole also contains a carboxy group, we also prefer to convert this group to the carbobenzoxy group prior to aroylation. The benzyl moiety of this group is then removed in the subsequent hydrogenolysis.

Table A contains results illustrating the antiinflammatory activity of a number of the compounds of the present invention, as determined by the inhibition of edema formation in the hind paw of rats (Charles River Strain; average weight I g.) in response to a sub-plantar injection of carrageenin (rat-foot edema test). The experimental procedures followed are those of Winter et al., as reported in Proc. Soc. Exp. Biol., N.Y., l l l, 544 (1962) and J. Pharmacol. Exp. Therap., I41, 369 (l963).

In this test, unanesthetized adult male albino rats of lSO g. to g. body weight are numbered, weighed, and an ink mark placed on the right lateral malleolus. Each paw is immersed in mercury exactly to the ink mark. The mercury is contained in a glass cylinder, connected to a Statham Pressure Transducer. The output from the transducer is fed through a control unit to a alcrovoltameter. One volume of mercury displaced by the immersed paw is read. Drugs are given by gavage. One hour after drug administration, edema is induced by injection of 0.05 ml. of 1% solution of carrageenin into the plantar tissue of the marked paws. lmmediately thereafter, the volume of the injected foot is measured. The increase in foot volume 3 hours after the injection of carrageenin constitutes the individual response. The increase in volume of the feet of the drug-treated animals are compared with those just receiving vehicle alone.

TABLE A Anti-inflammatory Activity of Compounds of the Present Invention Rat Foot Edema Test Anti-inflammatory Activity of Compounds of the Present Invention Rat Foot Edema Test lnhibition Inhibition of Edema Dosage of Edema Relative Effectiveness Compound mg/kg 7! Compared to Aspirin l-henzoyl2-tril'luoromethyl- 100 42.2 0.59

5-melhylhenzimidazole l-henzoyl-2-trifluoromethyl- 100 55.2 0.86

5-chlorobenzimidazole l-hcnloyl-2-trifluoroaeetamido- 100 30.4 0.6 I

S-chlorohenzimidazole l(4'-chlorobenzoyl )-2-trifluoro- I00 l6. l 0.3 l

acetamido-S-chlorohenzimidazo|e I-henzoyl-Z-l 2'-carhoxyethyl 100 13.2 0.38

5-chlorohenzimidazole l'benz0yl-2methyl-5,6- I00 30.0 0.64

dimethoxybenzimidazole l-benzoyl-2-(2' pyridyl)- 100 22.4 0.32

bcnzimidazole l-( l' -naphthoyl)benzimida2ole I00 l8.7 0.31

l-[4'-(a-benzyloxycarbonyh- 100 19.4 0.40

mcthoxybenzoyll5,6- dimethylbenzotriazole l-(4'-dimethylaminobenzoyl)- 100 19.4 0.29

S-ehlorobenzntriazole l-henzoyl-5chlorobenzotriazole 100 44.0 0.62

l-( 3',4',5'-trimcthoxybcnzoyl 100 28.2 0.46

S-chlorohenzotriazole l-(2',6-dimethoxybenzoyly- I00 17.0 0.35

5-chlorobenzotriazole On the same day that the compound under investigation is being tested, the above test procedure is also conducted with a second group of animals using acetylsalicylic acid (aspirin) instead, and the effectiveness of LII some of the novel compounds prepared show no activity. in Table B are listed representative examples of novel compounds which were prepared, but which exhibited no pronounced activity in the R.F.E. screen.

dimethylbenzotriazole each compound is then expressed relative to aspirin.

While many of the novel compounds described herein exhibit significant anti-inflammatory activity, 60

A number of l-aroyl benzimidazoles and benzotriazoles previously described in the prior art that we have tested do not show any pronounced activity, with but one exception, as can be seen by examining Table C.

TABLE c Anti-inflammatory Activity of Some Known Benzimidazoles and Benzotriazoles Rat Foot Edema Test Inhibition Inhibition of Edema dosage of Edema Relative Effectiveness Compound mg/kg Compared to Aspirin l-henzoylbenzimidazole 100 24.l 0.54

l-(4'-methoxybenzoyl)- I00 5.4 0.12

henzimidazole TABLE C-Continued Anti-inflammatory Activity of Some Known Benzimidazoles and Bcnzotriazoles Rat Foot Edema Test Inhibition Inhibition of Edema dosage of Edema Relative Effectiveness Compound mg/kg Compared to Aspirin l-(4-dimcthylaminobenzoyl)- I 17.5 0.35

benzimidazole l-benzoylbenzotriazole 100 14.] 0.20

l-acetylbenzimidazole 100 ]6.6

l-(diphcnylearbamyh- 100 9.9 0.19

benzimidazole l-acetylbenzotriazole llll) .t)

l-acetyl-5-cl1loro- 100 2.4

bcmotriamle lixhilvils hypcrglyeemic activity in fills Indeed. I-benzoylbenzimidazole. the known parent described in the prior art. e.g., 5,6-

the instant invention show superior anti-inflammatory activity and are useful in alleviating the swelling and inflammation exhibited by arthritic and rheumatic subjects.

These compounds can be administered either alone or in combination with pharmaceutically-acceptable carriers. The proportion of active ingredient to carrier is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For oral administration in capsule form, preferred excipients are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are desired. the essential active ingredients are combined with emulsifying and/or suspending agents. Diluents such as ethanol, propylene glycol, glycerine and various combinations of diluents are employed. For parenteral administration, solutions of the active ingredients in combination with other solutes such as glycose or saline are used. Such aqueous solutions should be suitably buffered, if necessary, to render them isotonic.

The dosage required to reduce inflammation and swelling in arthritic and rheumatic subjects will be determined by the nature and extent of the symptoms and can be easily regulated by those skilled in the art. Generally, small dosages will be administered initially with a gradual increase in dosage until the optimum level is determined. It will generally be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a smaller quantity administered parenterally. In general, from about 0.02 to 200 mg. of active ingredient per kilogram of body weight administered in single or multiple dosage units effectively reduce inflammation and swelling in arthritic and rheumatic subjects.

Preparation of the Benzimidazoles Most of the l-unsubstituted benzimidazoles employed as precursors in the present invention have been dimethylbenzimidazole, 2-trilluoromethylbenzimidazole. The preparations of the remaining benzimidazole precursors are described below.

Z-Trifluoroacetamido-S-chlorobenzimidazole This compound is prepared by reacting 2-amino-5- chlorobenzimidazole and trifluoroacetic anhydride in pyridine according to the procedure of N. J. Leonard, D. Y. Curtain and K. M. Beck, J. Am. Chem. Soc., 69,

2459 (1947). Yield 74%; m.p. 3l5l6C.

Anal. Calc'd for CXAHQCIFQNQO: C, 4|.Ul: H. l 91'. N. l5.94. Found: C, 39.46; H. l 77; N, 16.23.

Using the appropriate reactants, the following com- Anal. Cale'd for C,.H,F;,N O,: C, 46.96; H. 2.19; N. l2.l7. Found: C, 46.21; H. 2.28; N. l2.03

(0.4771 ash).

Preparation of Other l-Unsubstituted Benzimidazoles 2-Trifluorobenzimidazoles containing methyl, halo. and carboxy groups in various positions of the phenyl ring, e.g., Z-trifluoromethyl-S-methylbenzimidazole, can be conveniently prepared by the methods of E. S. Lane, J. Chem. Soc., 534 (1955) and B. C. Bishop, A. S. Jones, and J. C. Tatlow, J. Chem. Soc., 3076 (1964).

Benzotriazole Precursors The l-unsubstituted benzotriazoles used in the present invention have all been described in the prior art.

The following examples are provided to more fully illustrate the present invention, but are not to be construed as limiting the scope thereof in any way.

EXAMPLE 1 Into a 100 ml., 3-necked flask, fitted with a mechanical stirrer, dropping funnel, and drying tube, is added 2.36 g (0.02 moles) of benzimidazole dissolved in 50 ml. of anhydrous tetrahydrofuran. Triethylamine (2.02 g., 0.02 moles) is added and the mixture is cooled to C.

While the mixture is stirred vigorously at 0C., 3.81 g. (0.02 moles) of l-naphthoyl chloride. dissolved in a small amount of tetrahydrofuran, -is added dropwise over a period of 15 minutes. The cooling bath is removed, and the reaction mixture is allowed to come to room temperature. After stirring the reaction mixture I-Aroylhenzimidazole m.p., C.

l-4-dimethylamino-5,6- 205-207 dimethylhcnzimidazole l-4"chloroben7.oy1-2- trifluoromethylbenzimidazole 1-benzoyl-2-2-pyridylbenzimidazole l-henzoyl-Z-trifluoromethyl-5-methy1- benzimidazole l-bcnzoyl-Z-trifluoromethyl-S-chlorobenzimidazole l-benzoyl-Z-trifluoromethyl-5-carboxybenzimidazole 1-4'-chlorobenzoyl-2-trifluoromethyl-S- carbox benzimidazole l-benzoy -2-trifluoroacetamide-S-chlorobenzimidazole l-4-chlorobenzoyl2- trifluoroacctamido- S-ehlorobenzimidazole l-benzoyl-2-mcthyl-5,6-

dimethoxybcnzimidazolc l-benzoyl-5,6-dimethylbenzimidazole l-( 3.4',5'-trimcthoxybcnzoyl)-5.6-dimethy1 benzimidazole 1(4'-mcthoxyhenzoyl )-2- methyl-5.6-dimcthoxybenzimidazole at room temperature for about 2 hours, the triethylam- 60 ine hydrochloride is filtered and washed with a small amount of tetrahydrofuran. The filtrate is evaporated,

Yield "/1 Employing the conditions and procedure of Example 1, 0.020 moles of benzimidazole is reacted with 0.020 moles of 3,4,5-trimethoxybenzoyl chloride. The yield of 1-3, 4', 5-trimethoxybenzoylbenzimidazole is m.p. l28l29C.

Anal. Calc'd for c,.H...N.,o.= C. 65.37; H. 5.16; N. 8.97. Found: C. 65.45; H. 5.15; N. 9.13.

EXAMPLE lll Employing the conditions and procedures of Example l, the l-benzoylbenzimidazoles tabulated in Table l are prepared from the appropriate benzoyl chlorides and l-unsubstituted henzimidazoles.

TABLE 1 Elemental Analysis Found Calculated C H H N EXAMPLE IV Employing the conditions and procedures of Example l, the l-aroyl benzimidazoles listed below are readily prepared from the appropriate l-unsubstituted benzimidazoles and benzoyl chlorides.

l-( 2 -chlorobenzoyl )-2-trifluoromethyl-5- methylbenzimidazole l-( 3 -c hlorobenzoyl )-2-trifluoromethyl-5- methylbenzimidazole l-( 4'-chlorobenzoyl )-2-trifluoromethyl-5- methylbenzimidazole l-( 2-bromobenzoyl )-2-trifluoromethyl-5- methylbenzimidazole l-( 4-bromobenzoyl )-2-trifluoromethyl-5- methylbenzimidazole l-benzoyl-2-trifluoromethyl-4-methylbenzimidazole l-( 4'-chlorobenzoyl )-2-trifluor0methyl-4- methylbenzimidazole l-( 3-bromobenzoyl )-2-trifluoromethyl-4- methylbenzimidazole l-benzoyl-Z-trifluoroacetamido-4- methylbenzimidazole' l-( 3 -chlorobenzoy.l )-2-trifluoroacetamido-4- methylbenzimidazole l-(4-bromobenzoyk )-2-trilluoroacetamido-4- methylbenzimidazole l-( 3 '-bromobenzoyl )-2-trifluoromethyl-5- carboxybenzimidazole l -benzoyl-2-tril'luoroacetamido-S- carboxybenzimidazole l-( 3 'ch lorobenzoyl )-2-triflu0roacetamido-5- carboxybenzimidazole l-( 2-bromobenzoyl )-2-trifluoroacetamido-5- carboxybenzimidazole l-( 2-bromobenzoyl)-2-trifluoromethyl-5- chlorobenzimidazole l-( 2 chlorobenzoyl J-Z-trifluoromethyl-S- chlorobenzimidazole l-benzoyl-2-trifluoromethyl-4-bromobenzimidazole l-( 2'chlorobenzoyl )-2-trifluoromethyl-4- bromobenzimidazole H 3'-hromobenzoyl )-2-trifluoromethyl-4- bromobenzimidazole l-( 3'-bromobenzoyl )-2-trifluor0acetamido-S- chlorobenzimidazole l-benzyl-2-trifluoroacetamido-4- bromobenzimidazole l-( 4-chlorobenzoyl )-2-trifluoroacetamido-4- bromobenzimidazole l-( 3 '-chlorobenzoyl )-2-trifluoroacetamido-4- bromobenzimidazole l-benzoyl-2,5.6-trimethylbenzimidazole l-( 3-dimethylaminobenzoyl )-2.5 ,6- trimethylbenzimida zole Similarly, -benzoyl-5,6-dimethoxybenzimidazole l-(4-d imethylaminobenzoyl )-5 ,6- dimethoxybenzimidazole l-( 4 '-dimethylaminobenzoyl )-2-methyl-5 .6- dimethoxybenzimidazole l-( 40-chlorohenzoyl )-2-( 2'-pyridyl )-benzimidazole l-( 2 '-bromobenzoyl )-2-( 2 '-pyridyl )-benzimidazole l-( 3'-bromobenzoyl )-2-trifluoromethylbenzimidazole EXAMPLE V A. Preparation of t-butyl-p-hydroxybenzoate One mole (138 g.) of p-hydroxybenzoic acid is dissolved in 1 liter of methyl isopropyl ketone. After addsively with 5% sodium bicarbonate solution and water.

After drying the ether solution over anhydrous magnesium sulfate, it is evaporated and the crude t-butyl-phydroxybenzoate is recrystallized from ether-ligroin. Yield 78 g. (40%); m.p. l30l32C.

Anal. Calcd for C H O Found:

Similarly. t-butyl oand m-hydroxybenzoate are prepared from oand m-hydroxybenzoic' acids, respectively.

B. Preparation of Benzyl (4-carboxyphenoxy)acetate To a solution of 3.9 g. (0.02 moles) of t-butyl-phydroxybenzoate contained in l5 ml. of anhydrous dimethylformamide is added. in small portions, 1 g. of a 50% suspension of sodium hydride in mineral oil. The resultant mixture is stirred and heated to 50C. When the evolution of hydrogen ceases, 4.2 g. (0.020 moles) of benzyl bromoacetate is added dropwise to the stirred reaction mixture over a period of 20 minutes. After stirring the resultant mixture at 50C. for 3 hours. it is cooled and filtered. The filtrate is evaporated and the oily residue of crude benzyl(4-carbo-t-butoxyphenoxy- )acetate is stirred with 20 ml. of trifluoroacetic acid at room temperature for 1 hour.

The reaction mixture is concentrated under vacuum with a rotary evaporator and the residue of benzyl (4-carboxyphenoxy)acetate is recrystallized from ethyl acetate-ligroin. Yield 4.2 g. (74%); mp. l32l34C.

(, h7.l2'. H. 4.9]. C. (17.17; H. 5.08.

Found:

C, 63.07; H. 4.3( C. 63.]7; H. 4.4

Anal. Calc'd for C H CKLI Found:

Likewise. benzyl (2-chlorocarhonylphenoxy)acetate and benzyl (3-chlorocarbonylphenoxy)acetate are prepared from benzyl (2-carboxyphenoxy)acetate and benzyl (3-carboxyphenoxy)acetate, respectively.

D. Preparation of l-[4'-(abenzyloxycarbonyl)methoxybenzoyl]-2-trifluorome thylbenzimidazole Z-Trifluoromethylbenzimidazole and benzyl (4- chlorocarbonylphenoxy)acetate are reacted according to the general procedure described in Example I.

The yield of l-[4'-(abenzyloxycarbonyl)methoxybenzoyll-2-trifluoromethylbenzimidazole is 52%; mp. l l4-l 15C.

Anal. Calcd for C HuFu z i Found:

C. 56.05' H, 3.05 N. C, 56 2.

Similarly, l-( 2 -a-carboxymethoxybenzoyl )-2-trifluoromethylbenzimidazole l-(3'-acarboxymethoxybenzoyl)-2-trifluoromethylbenzimidazole are prepared from l-[2-(abenzyloxycarbonyl)methoxybenzoyl1-2-trifluoromethylbenzimidazole and l-[3-(abenzyloxycarbonyl )methoxybenzoyl -2-trifluoromethylbenzimidazole, respectively.

EXAMPLE Vl Employing the conditions and procedures of Examples V-D and V-E, the l-aroyl benzimidazoles in Table ll, Column B, are prepared by reacting the benzyl (chlorocarbonylphenoxy)acetates listed in Table ll, Column A, with the appropriate l-unsubstituted benzimidazoles.

TABLE ll 5,6-Dimethylbenzimidazole is reacted with benzyl (4-chlorocarbonylphenoxy)acetate according to the general procedure of Example I to provide l-[4-(oz benzyloxycarbonyl)methoxybenzoyl}-5,6- dimethylbenzimidazole in 48% yield; m.p. l59l6()C.

Anal. Calc'd for c s zz z a Found:

Similarly, the following l-aroyl benzimidazoles can be prepared by reacting benzyl ('4-chlorocarbonylphenoxy)acetate with the appropriate l-unsubstituted benzimidazole.

l'[4-(a-benzyloxycarbonyl)methoxybenzoyl]-2.5,6-

trimethylbenzimidazole l-[4'-(tar-benzyloxycarbonyl)methoxybenzoyl]-5,6- dimethoxybenzimidazole l-[4-(a-benzyloxycarbonyl)methoxybenzoyll-2- methyl-5,b-dimethoxybenzimidazole B. Preparation of l-(4-a-carboxymethoxybenzoyl)- 5,6-dimethylbenzimidazole l-lydrogenolysis of benzyloxycarbonyl)methoxybenzoyl]-5,6-

' dimethylbenzimidazole according to the procedure of Example V-E provides l-(4-acarboxymethoxybenzoyl)-5,-dimethylbenzimidazole; m.p. l88l90C.

Anal. Calcd for cud 116N204: C, 66.66; H, 4.97; N,

Found: C, 66.26; H, 5.16; N, 8.64.

Similarly, the remaining benzyl esters listed in A above can be converted to their respective acids.

EXAMPLE Vlll p-Carbobenzoxybenzoyl chloride is prepared according to the procedure of H. Fahn and B. Seidel, Makromol. Chem., l9,'7l H959) and reacted with 5,6-

dimethylbenzimidazole according to the general procedure of Example I to give l-(4'-carboben2oxybenzoyl)- 5,o-dimethylbenzimidazole in yield; m.p. l47-l 50C.

Hydrogenolysis of l-(4-carbobenzoxybenzoyl)-5,6-

' dimethylbenzimidazole according to the procedure of Example V-E affords l-(4'-carboxybenzoyl)-5.6- dimethylbenzimidazole in 70% yield; m.p. 290-308C.

Benzyl (chlorocarhonylphenoxy)acctatc Benzyl (4-chlorocarhonylphcnoxy )acetatc l-Aroylbenzimidazole (2 '-pyridyl )bcnzimidazolc Bcnzyl (3-chlorocarhonylphenoxy )acclulc lrimethylhcnzimidazolc Bcnzyl (4-chlorocarhonylphcnoxy )acclutc Bcm'yl (4-chlorocarhonylphcnoxy )ucctatc 5.6dimethoxybunzimidazolc EXA M PLE Vll A. Preparation of benzyloxycarbonyl)methoxybenzoyl1-5 ,6- dimethylbenzimidazole Anal. Calc'd for C H N op C, Found: C.

EXAMPLE lX The l-aroyl benzimidazoles below can be prepared from p-carbobenzoxybenzoyl chlooride and the appropriate benzimidazoles according to the procedure of Example Vlll.

l-(4'-carboxybenzoyl )-5,b-dimethoxybenzimidazole l-(4'-carboxybenzoyl)-2-methyl-5.6- dimethoxybenzimidazole l-(4-carboxybenzoyl)-2,5,o-trimethylbenzimidazole EXAMPLE X A. 2-(2-Carbobenzoxyethyl)-5-chlorobenzimidazole Into a liter, 3-necked flask, fitted with a stirrer, dropping funnel, immersion thermometer, and reflux condenser, containing 250 m]. of benzyl alcohol, is added 22.5 g. (().l moles) of 2-(2'-carboxylethyl)-5- chlorobenzimidazole, prepared according to the procedure of A. T. James and E. E. Turner, J. Chem. Soc..

I515 (1950). To this stirred suspension at l0C., is

2-( 2-carboxyclhyl )-5-hromobcnzimidazolc 2-( Z'-carhoxycthyl )-5-brumohcn1imidamlc 2-( I.-carboxycthyl-S-bromohcnzimidazolc 2-( l' carboxycthyl )-5-muthylhcnzimidazolt:

2-( 2 carhoxyethyl )-5-mcthylhcnzimidzwolu 2-( 2-carboxycthyl l-5-mcthylhunzimida7ulc added dropwise 40 ml. of thionyl chloride. After the addition is complete, the mixture is slowly heated to 100C. and stirred at this temperature for 4 hours. The reaction mixture is cooled, 300 ml. of ether is added, and the mixture is stored in the refrigerator overnight. The crystals of the benzyl ester, i.e., 2-(2- carbobenzoxyethyl)-5-chlorobenzimidazole are filtered and dissolved in chloroform. The chloroform solution is washed successively with a 5% solution of sodium carbonate and water. dried, and evaporated. Recrystallization from chloroform-ligroin provides 9.6 g. (3l%) of pure product, m.p. l3l-l32C.

Anal. Calcd for C, H, -,ClN-,O C. 64.87; H. 4.80; N. 8.90. Found: C. 64.88; H. 4.65; N. 8.70.

Anal. Calc'd for C HCIN O C, 6212'. H. 3.98:1. ll 52. Found: C, ()2 26'. H. 4.3); N. ll 72.

Similarly, l-4-chlorobenzoyl-2-(2'-carboxyethyl)-5- chlorobenzimidazole and l-4'-bromobenzoyl-2-(2'- carboxyethyl)-5-bromobenzimidazole are prepared according to the above procedures using p-chlorobenzoyl chloride and p-bromobenzoyl chloride, respectively, instead of benzoyl chloride.

EXAMPLE XI The benzimidazoles in Column A of Table III, prepared according to the procedure of A. T. James and E. E. Turner. J. Chem. Soc., 1515 (1950), are reacted with the appropriate benzoyl chlorides in accordance with the procedure described in Example X to give the l-aroylbenzimidazoles in Table lll, Column B.

TABLE III EXAMPLE Xll A solution of-0.l0 moles of 2-(2'-carboxyethyl)-5- carboxybenzimidazole, prepared according to the procedure of A. T. James and E. E. Turner, J. Chem. Soc.. H15 (1950), in about 200 ml. of benzyl alcohol is treated with about 50 ml. of thionyl chloride in the manner described in Example X-A.

The resultant dibenzyl ester, i.e. 2-(2- carbobenzoxyethyl)-5-carbobenzoxybenzimidazole. is reacted with benzoyl chloride, according to the procedure described in Example I to give l-benzoyl-2-(2'- carbobenzoxyethyl)-5-carbobenzoxybenzimidazole.

Hydrogenolysis of this latter compound according to the procedure of Example V-E provides l-benzoyl-2- (2 -carboxyethyl )-5-carboxybenzimidazole.

l-(4'-Chlorobenzoyl)-2-(2'-carboxyethyl)-5- carboxybenzimidazole and l-(4-bromobenzoyl-2-(2- carboxyethyl)-5-carboxybenzimidazole can be similarly prepared by reacting p-chlorobenzoyl chloride and p-bromobenzoyl chloride, respectively. with 2-( 2'- carbobenzoxyethyl)-5-carbobenzoxybenzimidazole and hydrogenolyzing the resultant products according to the procedure of Example V-E.

EXAMPLE Xlll 'A. Preparation of l-aroyl benzotriazoles The l-benzoyltriazoles in Table [V are prepared by reacting the appropriate benzoyl chlorides and benzotriazoles according to the general procedure of Example l.

TABLE IV Elemental Analysis Yield Calculated Found l-Aroyl Bcnzotriazole m.p.. C. "/1 C H N C H N 1-(4'-carbobenzoxymethoxy- 130-31 85 69.38 5.10 10.12 69.43 5.08 9.82

hcnzoyl)-5.6-dimethylbenzotriazolc 1-hcnzoyl-S-chlorobenzo- 99-101 80 60.58 3.13 16.31 60.06 2.96 16.02

lriazole 1-(4'-dimcthylcmino- 1311-32 26 59.90 4.35 18.66 59.56 4.27 18.65

hcnzoyH-S-chlorohcnzolriazolc l-( 3'.4'.5'-trimclhoxy- 165'72 30 55.33 4.06 12.09 55.11 3.94 12.41

hunzoyl J-S-chlorohcnzotriamlc 1-( Z'.6'-dimcthoxy- 180-111 11 56.70 3.110 13.23 56.73 4.05 13.33

hcnzoyl )-chlorohcnzolriaznlc 1-(4'-ch1orohcnzoyl)-5- 134-311 62 53.45 2.41 14.314 53.70 2.76 14.19

chlorobenzotriazolu 1-(4"dimclhylaminohcnzof l1' 197-98 69.37 6.16 19.04 69.55 6.01 19.05

5 6-dimcthylhcnzotriazo c The l-benzoylbenzotriazoles listed below are conveniently prepared by reacting the appropriate benzotria- I zoles and benzoyl chlorides according to the procedure N of Example I. 1 N

1-benzoy1-S-bromobenzotriazole 1:0 1-( 3 '-dimethylaminobenzoyl )-5-bromobenzotriaz0le 1-(3,4,5-trimethoxybenzoyl)-5- bromobenzotriazole R 1-(2,6-dimethoxybenzoyl)-5-hr0mobenzotriazole wherein R, is OCH CO H.

- A 11' M 1. A compound selected from the group having the 3 a of L I wherein R ls 4 structural formula:

What is claimed is: 

1. A COMPOUND SELECTED FROM THE GROUP HAVING THE STRUCTURAL FORMULA:
 2. A compound of claim 1 wherein R8 is 4-OCH2CO2H. 